Sustained release oral formulations

ABSTRACT

Pharmaceutical composition capable of releasing a therapeutically effective dose of active agent, e.g., rivastigamine, in a time-controlled manner.

[0001] This invention relates to a controlled release oralpharmaceutical composition and more particularly to a unit dosage thatupon administration releases an active agent in a time-controlledfashion.

[0002] Controlled release formulations may be formulated with followingaspects in mind:

[0003] a) the time until the release of active agent (lag time or delaytime)

[0004] b) the rate of release of active agent (fast or slow)

[0005] c) the duration of release of active agent (long or short)

[0006] Such aspects may be observed in standard in vitro dissolutiontests, e.g., in water or if desired in body fluids, e.g., artificialgastric juices.

[0007] Little has been published on reliable time-controlled releaseformulations allowing a release at a pre-determined time of a single orrepeated doses of active agents. There exists a need for suchformulations which are commercially acceptable.

[0008] After extensive testing, we have now found that it is possible toproduce a pharmaceutical composition capable of releasing at a specifictime, i.e., with a time delay or lag time, a pharmaceutical active agentor active agent mixture, e.g., substantially independently of theconcentration and type of ions present in the gastro-intestinalenvironment, e.g., hydrogen ions and hydroxyl ions, i.e., independentlyof pH, phosphate ions, and also independently of enzymes, present intothe surrounding body fluid.

[0009] The present invention provides in one aspect a pharmaceuticalcomposition comprising a first component comprising a first active agentdose wherein on contact with water (or body fluid) 70 to 95% of saiddose is released in water within 3 to 4 hours, and a second componentcomprising a second active agent dose, a water soluble osmosis inducingagent and a water swellable excipient, said second component having awater (or body fluid) permeable coating which, in use upon penetrationby water, ruptures after a certain delay time, e.g., due to the swellingof the swellable excipient, and releases (at a pre-determined time) theactive agent (hereafter referred to additionally as pharmaceuticalcompositions of the present invention).

[0010] The present invention also provides a pharmaceutical compositioncomprising a first component comprising an active agent wherein 70 to95% of said active agent in first component is released in water within3 to 4 hours, and a second component comprising the active agent, awater soluble osmosis inducing agent and a swellable excipient in water,said second component having a coating which, upon penetration by theaqueous fluids, breaks after a certain period due to the swelling of theswellable excipient, and releases the active agent at a pre-determinedtime.

[0011] By “within 3 to 4 hours” is meant that at the end of a period of3 to 4 hours the specified dose of active agent, e.g., >80% or >85%, hasbeen released.

[0012] The active agent may be a single active agent or may be amixture. The active agent may be the same in the first and second dosesor different in each dose. Preferably the active agent is the same.

[0013] In one embodiment, the coating for the second component is afilm, e.g., semi-permeable membrane. The swellable excipient swells inpresence of water or body fluid which penetrates through the coating andcreates mechanical pressure within the second component thereby causingthe coating to rupture or break and the system to open, e.g., like a lidof a box. Also, the swellable excipient may act as an osmotic agentdrawing the water into the second component. The thickness of thecoating is one of the parameters that controls the time delay, with morecoating resulting in a longer time delay.

[0014] It will be appreciated that the term “rupture” preferably refersto breaching but it may also refer to any film system which rapidly(e.g. over 30 minutes or less) dissolves or disappears or changes itsproperties to permit egress of the active agent

[0015] In another aspect there is provided a controlled releaseformulation, e.g., the second component, for releasing an active agentdose after a lag time wherein the active agent is released 6 to 12hours, e.g., 8 hours, after ingestion.

[0016] The second component may be coated with two films. A first filmis directly in contact with the second component and is preferably asemi-permeable membrane. The second film may be a semi-permeable (e.g.,allowing the passage of e.g. water or active agent in one direction) orpermeable. The films used in this embodiment may be, e.g., 2 to 5 times,thinner than the one used in a one-film embodiment. Such a compositionmay provide if desired longer delay times for the second component witha good release of the second dose of active agent. It further providescertain advantages as, e.g., reducing the amount of coating used.

[0017] By “first component” is meant a component capable of releasingimmediately or in a controlled manner, e.g., sustained release, a firsttherapeutically effective dose of active agent when said first componentis put in contact with water or body fluids.

[0018] By “second component” is meant a component capable of releasingimmediately or in a controlled manner, e.g., sustained release, a secondtherapeutically effective dose of active agent when said secondcomponent is contacted to water or body fluids.

[0019] By “semi-permeable membrane” is meant a membrane suitable for thepassage of the water (or body fluid) into an active agent containingcore which is coated with said membrane and hinders egress of adissolved active agent out of the core.

[0020] By “film”, “film-coating” or “membrane” is meant, unless statedotherwise, a coating which is applied onto a core component, e.g., thefirst or second component.

[0021] By “delay time or lag time” is meant the duration of time betweenadministration of the composition and the release of an effective doseof active agent from the first or second component.

[0022] A person skilled in art will appreciate that various plasmaprofiles may be obtained by varying, e.g.,:

[0023] the composition of the first and/or second components, e.g., thenature and amount of excipients and/or active agent(s)

[0024] the delay time

[0025] the type of semi-permeable and/or non semi permeable membrane

[0026] the speed and nature of the active agent release onset (e.g.fast, slow, exponential, logarithmic, linear), which may depend on therate of rupture of the membrane.

[0027] The composition according to the invention may be used foradministrating a wide variety of active agents.

[0028] The composition according to the invention is suitable forexample for water-soluble and also water-insoluble, solid,pharmaceutical active ingredients, which may be inorganic or inparticular organic active substances, and are to be used in accordancewith their indication as analgesics, antipyretics, antirheumatics,sedatives, hypnotic agents, anti-epileptics, depressants and stimulants,anaesthetics, neuroleptic analgesics, antihistamines, antihypertensiveagents, anticoagulants, antithrombotic agents, psychopharmacologicalagents, psycholeptics, chemotherapeutic agents, e.g. antibiotics,sulphonamides, antituberculosis agents (tuberculostatic agents) or alsochemotherapeutic agents against tropical infections, diuretics,spasmolytics, cardiovascular agents, e.g. sympathomimetics,antihypertensive agents, cardiac stimulants, e.g. cardiac glycosides anddigitaloids, parenteral sugar therapeutics, analeptics acting on thecentral nervous system, geriatric agents, tonolytics (of striatedmuscles), anti-Parkinson agents, cytostatic agents, immunosuppressants,tonics and vitamins, according to B. Helwig (Moderne Arzneimittel),1980.

[0029] As antibiotics, penicillin, tetracycline, chlorotetracycline,bacitracin, nystatin, streptomycin, neomycin, polymicin, gramicidin,oxytetracyclin, chloramphenicol, erythromycin, rifampicin, cefazolin,cefoxitin, cefsulodin, cefotiam and mefoxin may be used, and aschemotherapeutic agents sulfamethazine, sulfamerazine, sulfamethizoleand sulfisoxazole may be used, as solid active ingredients for thepresentation according to the invention. In addition, e.g. as sedativesand hypnotic agents chloral hydrate, pentabarbital, phenobarnital,secobarbital, codeine and carbromal may be used, and as cardiacglycosides and digitaloids digitoxin and digoxin may be used, and assympathomimetics epinephrine may be used as the solid active substancein water-soluble form or water-insoluble form.

[0030] In particular, antipyretics, analgesics and antirheumatics may beused as the solid active ingredient in the presentation according to theinvention in suitable water-soluble form or water-insoluble form, forexample propyphenazone, aminophenazone, aspirin (ASA), antipyrine,methyl nifenazine, melaminsulfone, sulfenazone, phenacetin, pentazocine,lactophenin, paracetamol, quinine, flufenamic acid, mefenamic acid,tolfenamic acid, meclofenamic acid, niflumic acid, clonixin orclonixidin, flunixin, ibuprofen, suprofen, ketoprofen, fenoprofen,pirprofen, diclofenac, ibufenac, procticic acid, naproxen, cicloprofen,tolmetin, clopirac, tiaprofenic acid, oxaprozin, fenclozic acid,fentiazac, clidanac, fenclonac, fenoprofen, flurbiprofen, carprofen,sulindac, cinmetacin, fenbuten, etodolac, butifufen.

[0031] Most advantageously, psychopharmacological agents may be used asthe solid active ingredient in the presentation according to theinvention, e.g. neuroleptics, antidepressants, thymoleptics,thymerethical drugs and tranquilisers in water-soluble form orwater-insoluble form, such as thioridazine, imipramine, desimipramine,clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline,reserpine, aromazine, chlorpromazine, fluopromazine, methopromazine,trimeprazine, diethazine, promethazine, aminopromazine, mepazine,pipamazine and maprotiline.

[0032] In addition, antihypertensive agents, such as oxprenolol andmetoprolol may be used as the solid active ingredient in thepresentation.

[0033] In a preferred embodiment a composition according to the presentinvention is used for administering Rivastigmine (Exelon®) which isuseful in the treatment of patients with mild to moderately severedementia of the Alzheimer type, also known as Alzheimer's Disease.

[0034] Rivastigmine may be administered as the hydrogen tartrate (hta)in unit dosage form, e.g., an immediate release capsule, at a dose offrom 0.5 mg to 6 mg twice a day.

[0035] Little has been published in detail on Rivastigmine'sbiopharmaceutical properties in humans. it is rapidly and completelyabsorbed. We have found that it is metabolised mainly through hydrolysisby esterases, e.g., acetyl and butyryl cholinesterase and has a plasmahalf life of 1 hour. It is subject to pre-systemic and systemicmetabolism. We now have found that sustained release formulations ofRivastigmine may be produced with advantageous properties, e.g., bettertolerability. Suitable test may be effected in fasted beagle dogs.

[0036] According to the present invention, Rivastigmine may be used inthe form of the free base or a pharmaceutically acceptable salt thereof.Preferably the hydrogen tartrate (hta) is used.

[0037] The composition of the invention allows, e.g., the manufacture ofonce a day pharmaceutical oral forms for patients who have to take morethan one dose of an active agent per day, e.g., at specific times, sothat their treatment is simplified. With such compositions tolerabilitymay be improved, e.g., with Rivastigmine, and this may allow a higherstarting dose and a reduced number of dose titration steps.

[0038] In a further aspect the invention relates to a pharmaceuticalcomposition comprising rivastigmine adapted so that in use on oraladministration a therapeutically effective dose of rivastigmine isreleased only after 6 hours (hereafter referred to additionally aspharmaceutical compositions of the present invention).

[0039] In a further aspect the invention relates to a pharmaceuticalcomposition capable of releasing twice on administration atherapeutically effective dose of rivastigmine at different intervalsupon oral administration (hereafter referred to additionally aspharmaceutical compositions of the present invention).

[0040] In preferred pharmaceutical composition of the invention, a firsttherapeutically effective dose of rivastigmine is released within 3 to 4hours of ingestion and, subsequently, a second therapeutically effectivedose of rivastigmine is released 6 to 12, preferably 8 to 10 hours,after ingestion.

[0041] The first component may be produced, e.g., by any conventionalmethods to provide the desired controlled release characteristics. Itmay be produced in solid form, e.g., a tablet, (e.g., a matrix-tablet),coated particles (e.g., non-pareilles) or pellets, e.g., coated pellets.

[0042] In one embodiment of said first component, the active agent isincorporated in a hydrophilic substance forming a gel substance oncontact with water, e.g., which may be present in a ratio of from 10 to50%, e.g., 15 to 45%, by weight of the first component, e.g., in theform of a controlled release tablet formulation, e.g., a matrix-tablet.

[0043] Hydrophilic gel forming substances commonly used in tabletformulations may be used and reference is made to the extensiveliterature on suitable substances, see in particular Fiedler's “Lexiconder Hilfstoffe”, 4th Edition, ECV Aulendorf 1996 and “Handbook ofPharmaceutical Excipients” Wade and Weller Ed. (1994) the contents ofwhich are incorporated herein by reference.

[0044] Preferred hydrophilic gel forming substances which may be usedfor the first component include one or more natural, partially ortotally synthetic, anionic or, preferably, non-ionic hydrophilic gums,modified cellulose substances or protein aqueous substances such as, forexample, acacia, gum tragacanth, locust bean gum, guar gum, karaya gum,agar, peptin, carrageen, soluble and insoluble alginates,methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, sodium carboxymethylcellulose,carboxypolymethylene, gelatin. Preferred are cellulose which includemethylcellulose, hydroxypropylcellulose and especiallyhydroxypropylmethylcellulose and sodium carboxymethylcellulose.

[0045] Especially preferred hydrophilic gel forming substances which maybe used for the first component comprises high-viscosity hydrophilicswellable substances, e.g. substances having a viscosity in the range of10,000 to 200,000 mPa-s, e.g. 50,000 to 150,000 mPa-s, e.g., 100,000mPa-s. A preferred swellable substance which may be used ishydroxypropylmethylcellulose, e.g., Methocel, e.g., K100M (100,000mPa-s/2% solution in water at 20° C.), having a methoxyl content of,e.g., 15 to 30%, e.g., 19 to 24%, and a hydroxypropoxyl content of,e.g., 5 to 15%, e.g., 7 to 12%. Swellable substances with diverseviscosities may be prepared as disclosed in “Handbook of PharmaceuticalExcipients” Wade and Weller Ed. (1994).

[0046] The weight portion of hydrophilic gel forming substances in theformulation may be from 10 to 50%, e.g., 25 to 50%, preferably 40%.

[0047] Said first component may comprise 3 to 20%, e.g. 5 to 15%, e.g. 6to 13% by weight of the active agent, e.g., rivastigmine hydrogentartrate (hta).

[0048] It may be also convenient to incorporate in the first componentat least one of other soluble or insoluble pharmaceutical excipients astablet diluents such as calcium sulphate, calcium phosphate, lactose,mannitol, sucrose. For example, microcrystalline cellulose in granularpowder and/or fine powder may be incorporated e.g. from 10 to 50%. Forexample, microcristalline cellulose fine powder may be present in arange of 20 to 50%, e.g, 30 to 40% by weight of the first component andmicrocellulose granular powder in a range of 10 to 40%, e.g., 20 to 30%by weight of the first component.

[0049] At least one glidant, e.g., dispersed silicon dioxide, talc, maybe present in a range of 0.1 to 1% by weight of the first component andat least one tablet lubricant, e.g., magnesium stearate, stearic acid,hydrogenated castor oil, polyetheylene glycol, may also be present in arange of 0.1 to 1% by weight of the first component, preferably 0.5%.

[0050] For example, the first component in this specific embodiment mayhave the following active agent, e.g., rivastigmine, releasecharacteristic in water or artificial stomach juices (e.g. 0.1 N HCl):time (minutes) amount (percentage) 30 28-35 60 40-55 120 58-75 180 70-90240 80-95 300 88-98 360 >92

[0051] In a further embodiment of the first component, the active agentis incorporated in coated particles comprising a diffusion coating. Thecoating may be adapted to provide the controlled release of the activeagent. Coating aids, conveniently used in coating formulation may beused. These coatings may include further binders, lubricants, glidants,stabilising agents, fillers or diluents, surfactants and the like. Asdisintegrants one can particularly mention CMC-Ca, CMC-Na, crosslinkedPVP (Crospovidone, Polyplasdone of Kollidon XL), Alginic acid, sodiumalginate and guar gum, most preferably crosslinked PVP, Crospovidone,crosslinked CMC and Ac-Di-Sol.

[0052] As binders which may be used in these coatings one canparticularly mention polysaccharides, e.g. potato starch, wheat starch,corn starch, hydroxypropylmethylcellulose, e.g., products known underthe registered trade marks Avicel®, Filtrak®, Heweten® or Pharmacel®.

[0053] Preferably cores which may be used for the first component areinert and water soluble. Typically the diameter is about 0.5 to 1.5millimeters.

[0054] The coatings which may be used for the first component maycomprise for example a cellulose derivative, e.g., which may be appliedas a film. Common cellulose coatings may be used and reference is madeto the extensive literature on suitable diffusion controllingsubstances.

[0055] As a preferred cellulose coating for the first component, one mayuse a coating comprising ethyl cellulose and hydroxypropylmethylcellulose (hereafter HPMC).

[0056] The ethyl cellulose has preferably a molecular weight 10,000 to15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000, Daltons.It is preferably cellulose substituted by ca 2 to 3 ethoxy groups perunit saccharide. Preferably it has an ethoxy content of 44-51%.

[0057] Ethyl cellulose as used in the examples preferably is ethylcellulose N10 Brand Aqualon® N10 (available from Dow Chemicals Company).

[0058] Hydroxypropyl methyl cellulose has preferably a viscosity of from1 to 10 cps, e.g., 2 to 8 cps. Preferably it has a molecular weight offrom 10,000 to 1,500,000 Daltons, e.g., 100,000 to 1,000,000, e.g.,300,000 to 800,000. It is preferably cellulose substituted by ethyl andhydroxypropyl groups.

[0059] Hydroxypropyl methyl cellulose preferably has a viscosity of 3cps or 5 cps.

[0060] The particles may have a diffusion coating preferably comprisingethyl cellulose and hydroxypropyl methylcellulose, e.g., in a ratio offrom 15:1 to 1:1, e.g., from 9:1 to 1:1, e.g., from 8:1 to 2:1, e.g.,from 7:1 to 3:1.

[0061] The particles may have a drug (active agent) coating preferablycomprising hydroxypropyl methylcellulose. The drug coating may containabout 50 to 90% by weight of said active agent, e.g., rivastigmine, forexample from 50 to 80% by weight of rivastigmine. The amount of drug maycomprise, e.g., 3-15% of the core.

[0062] Typically, the drug coating to diffusion coating ratio is from3:1 to 1:1.

[0063] If desired a protective coating may be present between thediffusion coating and the drug coating. It may comprisehydroxypropylmethylcellulose or ethyl cellulose. The protectivecoating/diffusion coating ratio may be, e.g., from 1:1 to 1:10, e.g.,from 1:2 to 1:8.

[0064] Silica may be present, e.g., in 10 to 70% by weight of the filmcoating.

[0065] For example, the first component in this specific embodiment mayhave one or more, e.g., all of the following active agent, e.g.,rivastigmine, release characteristic in water or artificial stomachjuices (e.g. 0.1 N HCl): time (minutes) amount (percentage) 30 25-40 6045-65 120 65-85 180 75-95 240 75-96 300 85-97 360 87-98 420 90-98 48090-99

[0066] As a further example, the first component in this specificembodiment may have the following active agent, e.g., rivastigmine,release characteristic in water or artificial stomach juices (e.g. 0.1 NHCl): time (minutes) amount (percentage) 30  5-25 60 25-45 120 50-70 18065-80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95

[0067] In a further embodiment of the first component, the active agentis incorporated into pellets, e.g. extruded pellets, which may be coatedwith a diffusion coating as previously described. The pellets maycomprise the active agent, e.g., rivastigmine, in the same form as forthe particles. It may further comprise binders as those mentioned aboveand diluents as calcium sulphate, calcium phosphate, lactose, mannitolor sucrose.

[0068] For example, the first component in this specific embodiment mayhave one or more, e.g., all of the following active agent, e.g.,rivastigmine, release characteristics in water or artificial stomachjuices (e.g. 0.1 N HCl): time (minutes) amount (percentage) 30  1-40 6010-60 120 40-80 180 60-90 240 65-95 300 70-99 360 75-99 420 >80

[0069] It may have preferably the following release characteristics:time (minutes) amount (percentage) 30 1-8 60 15-25 120 45-70 180 75-90240 92-95 300 95-98 360 97-99 420 >99

[0070] The present invention further relates to a controlled releaseoral pharmaceutical composition comprising a therapeutically effectivedose of Rivastigmine and pharmaceutically acceptable excipients, e.g.,the first component (hereafter referred to additionally aspharmaceutical compositions of the present invention).

[0071] The present invention further relates to a controlled releaseoral pharmaceutical composition comprising a therapeutically effectivedose of Rivastigmine wherein in use 50 to 95%, e.g., 50 to 80%, 60 to90%, 70 to 95%, of rivastigmine is released in water or body fluids,e.g., artificial stomach juices within 3 hours (hereafter referred toadditionally as pharmaceutical compositions of the present invention).

[0072] The delay time for the second component may be determinedprecisely, e.g.,:

[0073] by the type and amount of water soluble excipients in the core

[0074] by the water permeability and the number of film(s) coated on thesecond component

[0075] by the mechanical strength, i.e., elasticity and tearingstrength, of the film,

[0076] by the type and amount of swellable excipient incorporated in thecore.

[0077] An appropriate coating for the second component may be asemi-permeable membrane which is adapted to allow in use the passage ofwater (in use gastrointestinal juices) into the core and to hindersegress of the dissolved active agent out of the core.

[0078] Water is drawn through the semi-permeable membrane at a ratewhich may be controlled by the composition of the membrane. The waterwhich has penetrated the core dissolves at least part of the activeagent. Osmotic pressure is thereby produced. The greater the pressure,the more molecules or ions go into solution, until under normalcircumstances a saturated solution is produced.

[0079] In one embodiment, upon penetration by water or body fluid, theosmotic pressure, which as a consequence also induces swelling of theswellable excipient, may be produced by the active agent, e.g.,rivastigmine, itself. However, a carrier which is soluble in water maybe added in order to produce the necessary osmotic pressure. In thisway, the osmotic pressure necessary for inducing the operating principleof the second component can be attained in such a way that the bodyfluid entering to balance the osmotic gradient produces the desiredswelling of the swellable excipient (disintegrant) and after a certaindelay time the rupturing or breaking of the film coating allows therelease of the active agent. By optionally adding a water-solublecarrier in the core of the tablet, the second component may be producedin almost pH-independent form, i.e., independent of the concentration ofhydrogen ions and hydroxyl ions and/or independent of other ions, suchas phosphate ions, and also enzymes, for example in the alimentarytract.

[0080] Appropriate semi-permeable membranes for the film layer includethe semi-permeable membranes described in literature, for example inU.S. Pat. Nos. 3,916,899 and 3,977,404, which are suitable for passageof the water (body fluid) and not the dissolved active agent and arethus suitable for bringing about osmosis. For example, artificiallyproduced membranes may be used, which consist of cellulose acetate,cellulose triacetate, agar acetate, amylose acetate, cellulose acetateethyl carbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetatechloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methylsulphonate, cellulose acetate butyl sulphonate, cellulose ether,cellulose acetate propionate, cellulose acetate diethylamino acetate,cellulose acetate octate, cellulose acetate laurate, methyl cellulose,cellulose acetate-p-toluenesulphonate, hydroxylated ethylene vinylacetate, cellulose acetate butyrate and of other cellulose acetatederivatives. Other appropriate semi-permeable membranes are alsohydroxypropylmethyl cellulose and polymeric epoxides, copolymers ofalkylene oxide and alkyl glycidyl ether, polyglycols or polylactic acidderivatives and further derivatives thereof. In addition, mixtures mayalso be used, e.g. of water-insoluble acrylates, e.g., copolymer ofethyl acrylate and methyl methacrylate.

[0081] Generally, all semi-permeable membranes which are known fromliterature and have water-permeable properties are suitable forproducing the film for the second component.

[0082] Coating of, e.g., tablets, e.g., compressed tablets, coreparticles or pellets, with a film comprising, e.g., a semi-permeablemembrane of required thickness, may be effected in fluidised beds,coating pans or coating may be effected using, e.g., tabletting machines(dry coated tablet).

[0083] The second component may for example also be contained in acapsule, e.g., a gelatin capsule, which contains the active agent, e.g.,rivastigmine, a swellable excipient, optionally a water-soluble carrierand other excipients, such as lubricants and sustained release agents inpowder form, and is coated with the semi-permeable membrane as a film.

[0084] Appropriate films which may be used as a second coating for thesecond component include membranes which may be permeable orsemi-permeable to water or body fluid, e.g., sustained releasemembranes, as described in literature. This second film-coating may beapplied in the same manner as for the first film.

[0085] A preferred second film-coating for the second componentcomprises ethylcellulose, e.g., Ethylcellulose Brand Aqualon® N10(available from Dow Chemicals Company). It may be applied, e.g., byspraying a solution comprising Ethylcellulose and HPMC 5 cps in a weightratio of from e.g., 15:1 to 1:1, e.g., 9:1 to 1:1, e.g., from 8:1 to2:1, e.g., from 7:1 to 3:1.

[0086] The ethyl cellulose has preferably a molecular weight 10,000 to15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000, Daltons.It is preferably cellulose substituted by ca 2 to 3 ethoxy groups perunit saccharide. Preferably it has an ethoxy content of 44-51%.

[0087] Hydroxypropyl methyl cellulose has preferably a viscosity of from1 to 10 cps, e.g., 2 to 8 cps, preferably 3 cps or 5 cps. Preferably ithas a molecular weight of from 10,000 to 1,500,000 Daltons, e.g.,100,000 to 1,000,000, e.g., 300,000 to 800,000. It is preferablycellulose substituted by ethyl and hydroxypropyl groups.

[0088] In a preferred embodiment, the weight ratio between the first andthe second film applied on the second component is 20:1 to 1:5, e.g.,15:1 to 1:1, e.g., 10.1 to 2:1.

[0089] In a preferred embodiment of the invention, the film thicknessfor the second component may be in a range of from 50 to 800 micrometers(μm), e.g., 100 to 600 μm. For a second component having one film apreferred thickness is in the range of from 300 to 500 μm, e.g., 350 to400 μm. For a second component having two films a preferred thickness isin the range of from 100 to 300 μm, e.g., 150 to 200 μm.

[0090] The nature and the amount of the excipients and the active agentof the second component (excluding film-coating(s) to be ruptured) maythe same or not as the first component.

[0091] Suitable swellable excipients or disintegrating agents for thesecond component may be inert substances which swell rapidly uponcontact with aqueous liquids, e.g., alginic acid and derivatives,agar-agar, cellulose such as microcrystalline or microfine cellulose,methyl cellulose, crosslinked carboxymethyl cellulose, carboxymethylstarch, modified starch, crosslinked polyvinyl polypyrrolidone,Colloidal silicon dioxide, high molecular weight polymers comprisingethylene oxide, bentonite, Veegum, montmorillonite, dried citrus pulp,xylans and also cationic and anionic exchangers such as cholestyramines.

[0092] Further excipients may be used to produce or induce the osmosisin the swelling process in the second component are water-solublecarriers (osmosis-inducing substances), e.g., substances that do notirritate the gastric or intestinal mucous membranes, e.g. inorganic ororganic salts such as sodium chloride, sodium hydrogen phosphate, sodiumnitrate and sodium acetate, or also acids such as tartaric, citric oralso succinic acid and also sugars, especially e.g. mannitol, glucose,fructose, lactose and dextran compounds with different molecularweights. The amount of carrier may vary from a fragment to many timesthe quantity of rivastigmine employed.

[0093] The lubricants which may be an optional further excipient for thesecond component may be e.g., magnesium stearate, silicon aerogel, talc,stearic acid, hydrogenated castor oil, polyethylene glycol (PEG).

[0094] Optional additives for the second component may be, e.g.,anti-oxidants, e.g, a-tocopherol or butylated hydroxytoluene (BHT).

[0095] Optional additives in film coating for the second component maybe, e.g., pigments such as coloured iron oxides or titanium dioxideand/or flavourings, e.g., sweeteners, e.g., saccharine, Na cyclamate orsugar.

[0096] A preferred second component comprises, e.g., (weight %): CoreRivastigmine hta 0.5 to 25%  Sodium Chloride 10 to 35% Avicel PH 102  5to 25% PVPP-XL 20 to 70% a-tocopherol 0.01 to 5%   Aerosil 200  1 to 15%Magnesium Stearate 0.1 to 5%   First Coating: Cellulose Aceate  1 to 20%HPMC 0.1 to 1%   Second Coating: Ethylcellulose 0.5 to 10%  HPMC 0.1 to2%  

[0097] The invention further relates to a pharmaceutical compositioncomprising a core coated with two films, the first inner film being asemi-permeable to water or body fluids film applied directly on saidcore and comprising cellulose acetate, e.g., cellulose acetate E320 or398-10, the second outer film being a permeable to water or body fluidsfilm comprising ethylcellulose, e.g., Ethylcellulose N10.

[0098] The cores in question, comprising the active agent, e.g.,rivastigmine, and excipients, e.g., may be the compressed tablets,capsules and pellets that are usual in galenics and may be produced byknown processes. For example, the tablet mass may be produced by mixingthe active agents disintegrant and optional further excipients, such ascarriers, lubricants and if desired also sustained release excipients asrequired. Production of the compressed tablets and pellets may beeffected, e.g., using the tabletting machines which are known for thepreparation of for example round and rod-shaped compressed tablets andpellets, and the capsules are filled using known capsule fillingmachines.

[0099] The sustained release excipients that are used may be essentiallywater-insoluble excipients or mixtures thereof, e.g., lipids, inter aliafat alcohols, e.g. cetyl alcohol, stearyl alcohol and cetostearylalcohol; glycerides, e.g. glycerin monostearate or mixtures of mono, di-and triglycerides of vegetable oils; hydrogenated oils, such ashydrogenated castor oil or hydrogenated cottonseed oil; waxes, e.g.beeswax or carnauba wax; solid hydrocarbons, e.g. paraffin or mineralwax; fatty acids, e.g. stearic acid; certain cellulose derivatives, e.g.ethyl cellulose or acetyl cellulose; polymers or copolymers, such aspolyalkylenes, e.g. polyethylene, polyvinyl compounds, e.g. polyvinylchloride or polyvinyl acetate, as well as vinyl chloride—vinyl acetatecopolymers and copolymers with crotonic acid or polymers and copolymersof acrylates and methacrylates, e.g. copolymers of ethyl acrylate andmethyl methacrylate.

[0100] A person skilled in the art may use other excipients than thosedisclosed above to obtain the desired effect. Reference is made to theextensive literature on suitable excipients provided in the art inparticular Fiedler's “Lexicon der Hilfstoffe”, 4th Edition, ECVAulendorf 1996 and “Handbook of Pharmaceutical Excipients” Wade andWeller Ed. (1994) the contents of which are incorporated herein byreference.

[0101] As already stated initially, the release which is to be effectedat different time intervals may be controlled precisely by thecomposition and the layer thickness of the coating (film) used for thesecond component, mechanical strength and elasticity and optionallythrough the quantity and swelling property of the swelling ordisintegrating agent.

[0102] The second component, e.g., with one film, according to theinvention may have one or more, e.g., all of the following releasecharacteristics in water: time (minutes) amount (percentage) 0 0-1 1200-1 180 0-1 240  0-85 300  0-97 360 >99.5

[0103] The second component, e.g., with two films, according to theinvention may have one or more, e.g., all of the following releasecharacteristics in water: time (minutes) amount (percentage) 0 0-1  1200-1  180 0-1  240 0-85 300 0-97 360   0-99.5 420  0-100 480 70-100 54075-100 600 85-100 660 90-100 720 >50

[0104] The rupture time may lead to 85% or more, e.g., 90%, of theactive agent in the second component released within 30 minutes.

[0105] The pharmaceutical composition according to the inventionpreferably comprises from 0.5 to 25%, e.g., 1 to 10%, e.g., 2 to 5%, byweight of rivastigmine of the total composition.

[0106] The pharmaceutical compositions of the present invention areuseful in the known indications of the particular active agentincorporated therein.

[0107] The exact amounts of active agent doses and of the formulation tobe administered depend on a number of factors, e.g., the condition to betreated, the desired duration of treatment and the rate of release ofactive agent.

[0108] For example, the amount of the active agent required and therelease rate thereof may be determined on the basis of known in vitro orin vivo techniques, determining how long a particular active agentconcentration in the blood plasma remains at an acceptable level for atherapeutic effect.

[0109] For example, for rivastigmine, dosages in the range of 1 mg to 12mg of active agent per day for a 70 or 75 kilogram mammal, e.g., humans,and in standard animal models, may be used. A surprisingly increasedtolerability of rivastigmine provided by the compositions may beobserved in standard animal tests and in clinical trials.

[0110] The pharmaceutical compositions of the invention are, e.g.,administered, e.g., orally once-a-day, if two active agent doses arepresent and twice-a-day if a second active agent dose is present.

[0111] In a further aspect, the present invention provides the use of anactive agent, e.g., rivastigmine, and excipients as defined above in themanufacture of a medicament for a once-a-day treatment of patients with,e.g., mild to moderately severe Dementia of the Alzheimer's type by oraladministration.

[0112] In the following non-limitative examples, the invention is morefully clarified. If not otherwise stated, the parts are parts by weight.Temperatures are given in degrees Celsius.

Preparation of the First Component

[0113] The first component may be produced in conventional manner bymixing the components. Below are examples of specific forms of firstcomponent allowing various release profile of the active agent containedtherein.

EXAMPLE 1 First Component in the Form of a Matrix Tablet

[0114] The resultant mixture may be in powder form which may be pressedto form a tablet in conventional tabletting machines at compressionpressures of, e.g., 2000 to 16000 lbs/sq.in.

[0115] A. Preparation of a Granulate:

[0116] Ingredients

[0117] rivastigmine, e.g., hta

[0118] microcrystalline-cellulose, e.g., fine powder

[0119] purified water for dissolving the drug substance

[0120] Rivastigmine hta is dissolved in 10 to 20%, e.g., 16.3% by weightof purified water of the total granulate and the solution stirred untilclear. A crossbar stirrer may be used at, e.g., 150-200 rpm, e.g., 180rpm for 10-20 minutes, e.g., 15 minutes.

[0121] Microcrystalline-cellulose fine powder is sieved, e.g., through amanual or vibration sieve fitted with a screen and having a mesh widthof, e.g., 1600 micrometers, and a wire diameter of, e.g., 500micrometers, into a vessel of, e.g., a Collette Gral® 10 high shearmixer.

[0122] At mixer setting I and chopper setting I, the powder is wetgranulated in the high shear mixer with the aqueous drug substancesolution (granulation liquid) which is added at a rate of 0.5 to 1l/min, e.g. 0.75 l/min.

[0123] The dissolving vessel (used for the preparation of thegranulation liquid) is rinsed with the purified water and the rinsingliquid added at mixer setting I and chopper setting I at a rate of 0.5to 1 l/min, e.g. 0.75 l/min.

[0124] The chopper setting is then increased to II and approximately 1minute mixing is applied. The granulation stopped and the wall of theCollette Gral® vessel cleaned. The wet granulate is mixed for anadditional minute at mixer setting I and chopper setting II.

[0125] The wet granulate is then dried by e.g. transferring it from thehigh shear mixer to a fluidized bed dryer bowl and applying an inlet airtemperature from 40 to 60° C., e.g. 50° C., until a LOD (loss ofdensity) of 2.5-5.0% is reached (corresponding to a product temperatureof approx. 31° C.).

[0126] The dried granulate is then broken by e.g., passing it through anoscillator with a screen (e.g. mesh width 800 micrometers and wirediameter 320 micrometers) into the container of a free fall mixer (e.g.Turbula® T10A).

[0127] B. Preparation of the Tablet Mixture:

[0128] Ingredients

[0129] hydroxypropylmethyl-cellulose K100M

[0130] microcrystalline cellulose, e.g., granular powder

[0131] highly dispersed silicon dioxide

[0132] Microcrystalline-cellulose (MCC) granular powder,hydroxypropylmethyl-cellulose and silicon dioxide highly dispersed maybe premixed manually in a plastic bag or in a free fall mixer forapproximately two minutes. The silicon dioxide may be dispersed into theHPMC and MCC in order to reduce any dedusting during the subsequentsieving step.

[0133] The pre-mixture may be sieved by passing it through a sieve (orvibration sieve). The mesh width used may be, e.g., 800 micrometers andwire diameter 320 micrometers.

[0134] The dry pre-mixture may be transferred into the container of thefree fall mixer (e.g. Turbula® T10A) and mixed with the granulate until100 rotations are reached, e.g., 20 rpm for 5 minutes.

[0135] Magnesium stearate may be manually premixed with about 10 partsof the dry pre-mixture in plastic bag or in a free fall mixer for abouttwo minutes. The magnesium stearate may be dispersed in order to preventany re-agglomeration after the subsequent sieving step.

[0136] The premixture may be sieved by, e.g., passing it manuallythrough a sieve (or vibration sieve). The mesh width used may be forexample 800 micrometers and the wire diameter 320 micrometers.

[0137] The magnesium stearate pre-mixture is transferred into, e.g., thecontainer of a free fall mixer (e.g. Turbula® T10A) containing the restof pre-mixture and the whole tablet mixture is mixed until 100 rotationsare reached, e.g., at 20 rpm for 5 minutes.

[0138] C. Tabletting

[0139] Tablets are formed by compression on, e.g., an excentic singlepunch tabletting machine (e.g. Comprex®) or a rotary tablet press (e.g.,Betapress®, Korsch® PH250) using, e.g., 6 mm punches (round, convex,bevelled edges).

[0140] Non-limitative examples of the first component which may beprepared by the process disclosed above are provided in the followingtable: Composition No. 1 2 3 rivastigmine hta (mg) 7.2 7.2 7.2micocristalline cellulose fine powder (mg) 25.95 25.95 25.95hydroxypropylmethylcellulose K100M (mg) 18.75 22.50 30.05microcristalline cellulose granular powder 22.35 18.60 11.05 (mg)magnesium stearate (mg) 0.375 0.375 0.375 silicon dioxide highlydispersed (mg) 0.375 0.375 0.375 Total weight 75 mg 75 mg 75 mg

[0141] The compositions No. 1, 2 and 3 provide the following releaseprofile when dissolved into water: Composition 1: Time (min.) 30 60 120180 240 300 360 420 480 Drug release (%) 29.3 42.6 60.5 73.3 82.6 89.493.5 96.4 97.8 Composition 2: Time (min.) 30 60 120 180 240 300 360 420480 Drug release (%) 33 51.9 72.6 84.5 92.3 96.8 98.9 99.9 100Composition 3: Time (min.) 30 60 120 180 240 300 360 420 480 Drugrelease (%) 32.1 46 64.3 77.6 85.5 91.7 95.1 97.2 97.8

EXAMPLE 2 First Component in the Form of Coated Particles

[0142] The preparation protocol of the film solutions is givenhereafter. A non-limitative Example of a composition obtained accordingto this protocol will illustrate the invention.

[0143] A/ Ingredients:

[0144] The ingredients for the preparation of the film solutions areprovided in the following table: Component Comment Supplier Rivastigminehta rivastigmine Novartis hydrogen tartrate Non-pareilles sugar spheresH. G. Werner 0.85-1.0 mm (USP) HPM-cellulose 3 Hydroxypropyl Shin-EtsuChemicals Co. methylcellulose 3 cps Ltd. Ethylcellulose N10Ethylcellulose N10 Dow Chemicals Company HPM-cellulose 5 HydroxypropylDow Chemicals Company methylcellulose 5 cps Aerosil 200 silicon dioxideDegussa AG highly dispersed Magnesium — FACI SRL stearate Hardgelatinesize 3, Cap + Body: Capsulgel N.V. capsules rich yellow opaque, CONISNAP6 dimple

[0145] B/ Preparation of Film Solutions

[0146] The % are expressed by weight of the solution prepared (qsp.purified water for 1, 2 and 3).

[0147] 1. Preparation of the aqueous HPMC-solution (5%)

[0148] HPMC 3 cps is dispersed in purified water in a stainless steelvessel while stirring approximately 2 min at 500 rpm in a crossbarstirrer. The solution is stirred until clear (30 min) at a speed of 250rpm. The obtained solution is allowed to stand still for 12 h in astainless steel vessel.

[0149] 2. Preparation of the aqueous Rivastigmine/HPMC film solution

[0150] Rivastigmine hta (15-25%) is dissolved in the HPMC-solution(3-5%) while stirring (Rivastigmine/HPMC solution). The solutionobtained is stirred until clear (approx. 15 min) in a stainless steelvessel (crossbar stirrer speed: 250 rpm). Then, silicon dioxide (1-3%)is dispersed in the Rivastigmine/HPMC-solution while stirring in astainless steel vessel (crossbar stirrer speed: 250 rpm). The solutionobtained is stirred for approximately 10 minutes. If needed the silicondioxide may be dispersed in 2 parts of the Rivastigmine/HPMC-solutionusing a mortar and pestle before adding the rest of the solution.

[0151] 3. Preparation of the aqueous HPMC film solution

[0152] Silicon dioxide (1.5-3%) is dispersed in the HPMC-solution 3 cps(3-7%) while stirring in a stainless steel vessel (crossbar stirredspeed: 250 rpm). The solution is stirred for approximately 10 minutes.If needed, the silicon dioxide is dispersed in 2 parts of theRivastigmine/HPMC-solution using a mortar and pestle before adding therest of the solution.

[0153] 4. Preparation of the organic solvent

[0154] Ethanol 94% (w/w) and acetone are mixed (see proportions inparagraph 5) during approximately 2 minutes in a stainless steel vesselacetone (crossbar stirrer speed: 250 rpm).

[0155] 5. Preparation of the organic polymer film solution

[0156] Ethylcellulose N10 (5-10%) and the HPMC 5 cps (0.5-2%) aredispersed in a stainless steel vessel in the organic solvent (acetone(45-65%) and ethanol 94%(35-45%)) while stirring approximately 1 minutein a crossbar stirrer speed: 500 rpm stir the solution until clearapproximately 30 minutes (speed: 250 rpm) in stainless steel vessel. Thesolution is let stand still for 12 h.

[0157] C/ Coating

[0158] 1. Aqueous coating

[0159] A fluidized bed dryer Glatt WST 5 (batch size: approximately 1.5kg) is adjusted to the required inlet air temperature (60° C.) and thespray rate to 15 g/min (pressure: 2.5 bar) by means of the variation ofthe peristaltic pump with a silicon tube (internal diameter 4.0 mm). TheWurster column (6 inch) with a binary spray nozzle (1.0-1.2 mm diameter)in the center of the base plate that sprays in line with the air stream,is pre-warmed to 45° C. The non-pareilles are added and the air flap isadjusted to the airflow required for gentle fluidization of thenon-pareilles inlet air quantity approximately 325 m³/h.). TheRivastigmine/HPMC-solution from step A is then sprayed immediately inorder to minimise abrasion of the no stainless steel vesselnon-pareilles. The product temperature is approximately 45° C.

[0160] Then, the stainless steel vessel and the silicon tubing arerinsed with the HPMC-solution 3 cps (approximately 25 g). For theprotective coating, the aqueous HPMC-solution is sprayed (rinsingliquid—first; the rest of the HPMC-solution—second). The stainless steelvessel and the silicon tubing are then rinsed with purified water(approximately 25 g) and then the rinsing water sprayed.

[0161] 2. Organic coating

[0162] A fluidized bed dryer Glatt WST 5 (batch size: approximately 1.5kg) is adjusted at the inlet air temperature (50° C.) and the spray rateto 25 g/min (pressure: 2.5 bar) by means of the variation of theperistaltic pump with silicone tube (internal diameter 4.0 mm). TheWurster column (6 inch) with a binary spray nozzle (1.0-1.2 mm diameter)in the center of the base plate that sprays in line with the air streamis used. The organic solvent is sprayed to remove the rest of thepurified water from the tubing system and the nozzles (to preventcrystallisation of ethylcellulose (organic polymer film solution) in thetubes). The product temperature is approximately 40° C.

[0163] Then, the organic polymer film solution is sprayed. The stainlesssteel vessel and the silicon tubing are rinsed with approximately 50 gof the organic solvent ethanol/acetone and the rinsing liquid issprayed. The coated non-pareilles are dried at an inlet air temperatureof 50° C. until the product temperature increases by 2° C.

[0164] The coated non-pareilles are dried manually in a Waldner traydryer (inlet air temperature: 30° C.) for 6 hours to remove any residueof the organic solvent from the coating and passed through a sieve(sieve size 1250 mm and wire diameter 400 mm) to remove agglomerates.

[0165] 3. Preparation of the capsule filing mixture:

[0166] Magnesium stearate is manually passed through a sieve having amesh width of 800 mm and a wire diameter of 320 mm. The sieved magnesiumstearate is then mixed with the coated pellets in a free fall mixer(Turbula 10I) at 20 rpm for 5 minutes, i.e., 100 rotations.

[0167] 4. Capsule filing

[0168] The capsule filling mixture is filled on a automatic capsulefilling machine (Zanasi LZ 5) into empty hardgelatine capsule shells(CONI-SNAP 6 dimple, size 3). The nominal fill weight is as mentionedabove.

[0169] The process parameters are as follows:

[0170] speed: 3000 HK/h

[0171] dosator/piston:

[0172] size: #4

[0173] height: 12-14 mm

[0174] vacuum:0.7 bar

[0175] feed hopper: none

[0176] D/ Preparation of a Composition of Exelon MR BID 4.5 mg HKP

[0177] The composition is prepared according to the process describedabove. The ingredients are given in the table below: weight weight PhaseComponents (mg) (mg) aqueous rivastigmine hta 7.20 7.20 drugsubstance/polymer hydroxypropyl 1.50 1.50 solution^(1,3) methylcellulose3 cps (drug loading) silicon dioxide 0.75 0.75 highly dispersed purifiedwater 28.50 28.50 aqueous polymer hydroxypropyl 1.50 1.50 solution^(1,3)methylcellulose 3 cps (protective coating) silicon dioxide 0.75 0.75highly dispersed purified water 28.50 28.50 organic polymersolution^(2,3) ethylcellulose N10 4.05 7.35 (diffusion coating)hydroxypropyl 0.45 3.15 methylcellulose 5 cps ethanol 94% (w/w) 16.2037.80 acetone 24.30 56.70

[0178] Composition of a capsule of Exelon MR BID 4.5 mg HKP Total filmquantity (% of the theoretical capsule 3.0 content (= 150 mg)) Diffusioncoating (ethylcellulose: hydroxypropyl 90:10 70:30 methylcellulose)Phase Component i) ii) Core non-pareilles (placebo) 134.40 129.15Coating 1 rivastigmine hta 7.20 7.20 (drug loading) hydroxypropyl 1.501.50 methylcellulose 3 cps silicon dioxide 0.75 0.75 highly dispersedCoating 2 hydroxypropyl 1.50 1.50 methylcellulose 3 cps (protectivecoating) silicon dioxide 0.75 0.75 highly dispersed Coating 3ethylcellulose N10 4.05 7.35 (diffusion coating) hydroxypropyl 0.45 3.15methylcellulose 5 cps lubricant magnesium stearate 0.15 0.15 Total fillweight 150.75 151.50 capsules CONISNAP size 3 49.00 49.00 TOTAL (mg)199.5 200.50

[0179] The following release profile is obtained Time (min.) 30 60 120180 240 300 360 420 480 Drug release i) 32.5 55.1 76.4 84.1 88.0 90.692.4 93.8 94.9 (% in 0.1 HCl) ii) 15.5 36.3 61.2 72.9 79.7 83.4 86.589.1 90.6

[0180] E/ Dosage Strengths:

[0181] For all dosage strengths the same coated non-pareilles (with thesame drug load) are used. Different dosage strengths (1.5 mg-9 mg) areobtained by varying the capsule fill weight, as outlined in the tablebelow. Dosage strengths capsule fill weight (approx.) capsule size 1.5mg  50 mg 4 3.0 mg 100 mg 3 4.5 mg 150 mg 3 6.0 mg 200 mg 2 9.0 mg 300mg 2

[0182] For the dosage strengths 6.0 mg, 3.0 mg and 1.5 mg, placebonon-pareilles could be added to optimise the filling degree of thecapsules if needed.

EXAMPLE 3 First Component in the Form of Coated Pellets

[0183] A/ Ingredients:

[0184] Rivastigmine hydrogen tartrate

[0185] Microcristalline cellulose Avicel® PH-101 (FMC Corporation,Philadelphia, USA)

[0186] Lactose 200 mesh (DMV, Vehgel, Netherlands)

[0187] Ethylcellulose N10 (Dow Chemicals Company, USA)

[0188] Hydroxypropyl methylcellulose 5 cps (Dow Chemicals Company, USA)

[0189] Magnesium stearate

[0190] Hardgelatine capsules: size 3, Cap+Body: rich yellow opaque,CONISNAP® 6 dimple (Capsulgel N.V.).

[0191] The amounts of the ingredients to be used are provided in theprotocol description or in paragraph G/ below.

[0192] B/ Preparation of the Drug and Film Solutions

[0193] The % mentioned below in 1, 2 and 3 are expressed by weight ofthe solution prepared:

[0194] 1. Preparation of the aqueous Rivastigmine solution

[0195] Rivastigmine is dissolved in water, e.g., in a stainless steelvessel, while stirring and the solution is stirred until clearapproximately 15 min at 250 rpm in, e.g., a crossbar stirrer. The amountof water is about 39% of the dry core weight which are prepared asdescribed below.

[0196] 2. Preparation of the organic solvent

[0197] Ethanol 94% (w/w) and acetone are mixed (acetone (60%)/ethanol94%(40%)) during approximately 2 minutes in a stainless steel vessel(crossbar stirrer speed: 250 rpm).

[0198] 3. Preparation of the organic polymer film solution

[0199] Ethylcellulose N10 (8%) and the HPMC 5 cps (2%) are dispersed ina stainless steel vessel in the organic solvent (90%) while stirringapproximately 1 minute in a crossbar stirrer (speed: 500 rpm). Thesolution is stirred until clear approximately 30 minutes (speed: 250rpm) in, e.g., stainless steel vessel. The solution is allowed to standfor 12 h.

[0200] C/ Preparation of the Pellets

[0201] The lactose and Avicel® are loaded in a Collette Gral® (10 or 25L) and mixed for 2 minutes (plow-slow, Chopper-slow). The rivastigminesolution is added into the mix of Avicel® and lactose in the ColletteGral® with the plow at slow speed (Chopper-off).

[0202] After the drug solution is pumped into the Collette Gral®,additional water is added to the same container for rinsing. Thequantity of the additional water is 18.5% of the dry weight of the core.This additional water is pumped into the mix from above with plow atslow speed (Chopper-off).

[0203] The mix from above is granulated in the Collette Gral® for about15 minutes (Plow slow, Chopper-off). The machine is stopped at 5 minuteintervals and the walls of the vessel scraped The chopper is turned onat slow speed for the last two to three minutes. The wet mass from aboveis extruded into thin strands (Parameters: Twin screw extruder fromGabler®, screen size: 1 mm, screw speed: 50 rpm, dosage machineposition: 1.8, pressure of the mass: 10 bar).

[0204] The extruded mass is spheronized, i.e., formed into pellets,using a 3 kg charge at a time (Parameters: Spheronizer from WyssPharmex®, charge in the spheronizer: 3 kg, rotational speed: 870 rpm,spheronization time: 6 minutes).

[0205] The wet pellets are dried (Parameters: Aeromatic® fluid beddrier, inlet air temperature: 60° C., exhaust temperature: 47 to 49° C.,dry to LOD (loss of drying) of 2.5 to 3.0%).

[0206] The dried pellets are manually sieved to exclude theagglomerates. All that passes through the sieve is collected for coating(sieve size: 1600 micrometers).

[0207] D/ Coating

[0208] 1. Organic coating

[0209] A fluidized bed dryer Glatt® WST 5 (batch size: approximately 1.5kg) is adjusted at the inlet air temperature (50° C.-325 m³/h) and thespray rate to 25 g/min (pressure: 2.5 bar) by means of the variation ofthe peristaltic pump with silicone tube (internal diameter 4.0 mm). TheWurster column (6 inch) with a binary spray nozzle (1.0-1.2 mm diameter)in the center of the base plate that sprays in line with the air streamis used. The organic solvent is sprayed to remove the rest of thepurified water from the tubing system and the nozzles (to preventcrystallisation of ethylcellulose (organic polymer film solution) in thetubes). The product temperature is approximately 40° C.

[0210] Then, the organic polymer film solution is sprayed. The stainlesssteel vessel and the silicon tubing are rinsed with approximately 50 g.of the organic solvent ethanol/acetone and the rinsing liquid issprayed. The coated pellets are post-dried at an inlet air temperatureof 50° C. until the product temperature increases by 2° C.

[0211] The coated pellets are dried manually in a Waldner® tray dryer oftype HW 15/2N (inlet air temperature: 30° C.) for 6 hours to remove anyresidue of the organic solvent from the coating and then passed througha sieve (sieve size 1600 micrometers and wire diameter 400 micrometers)to remove agglomerates.

[0212] E/ Preparation of the Capsule Filing Mixture:

[0213] Magnesium stearate is passed through a sieve having a mesh widthof 800 micrometers and a wire diameter of 320 micrometers. The sievedmagnesium stearate is then mixed with the coated pellets in a free fallmixer (Turbula® 10I) at 20 rpm for 5 minutes, i.e., 100 rotations.

[0214] F/ Capsule Filing

[0215] The capsule filling mixture is filled on a automatic capsulefilling machine (Zanasi® LZ 5) into empty hardgelatine capsule shells(CONI-SNAP® 6 dimple, size 3). The nominal fill weight is as mentionedabove (Process parameters: speed: 3000 HK/h, dosator/piston: size #4 andheight: 12-14 mm, vacuum: 0.7 bar, feed hopper: none).

[0216] G/ Composition of Exelon MR BID 4.5 mg HKP

[0217] The composition is prepared according to the process describedabove. Total film quantity (% of the theoretical capsule content 3.0 (=150 mg)) Diffusion coating (ethylcellulose: hydroxypropylmethylcellulose) 80:20

[0218] Phase Component weight (mg) Core rivastigmine hta 7.20 lactose200 mesh 60.30 microcristalline cellulose (Avicel ®) 67.5 Diffusioncoating ethylcellulose N10 3.24 hydroxypropyl methylcellulose 5 cps 0.81lubricant magnesium stearate 0.15 Total fill weight 139.20 capsulesCONISNAP ® size 3 49.00 TOTAL 188.20

[0219] The following release profile is obtained: Time (min.) 30 60 120180 240 300 360 420 Drug release 4.2 21.9 57.8 84.8 94.5 97.9 99.4 99.9(% in 0.1 N HCl)

[0220] H/ Dosage Strengths:

[0221] For all dosage strengths the same pellets (with the same drugload) are used. Different dosage strengths (1.5 mg-9 mg) are obtained byvarying the capsule fill weight, as outlined in the table below. Dosagestrengths capsule fill weight (approx.) capsule size 1.5 mg  46.4 mg 43.0 mg  92.8 mg 3 4.5 mg 139.2 mg 3 6.0 mg 185.6 mg 2 9.0 mg 278.4 mg 2

[0222] For the dosage strengths 6.0 mg, 3.0 mg and 1.5 mg, placebopellets could be added to optimise the degree of filling of the capsulesif needed.

Preparation of the Second Component

[0223] The second component may be produced in conventional manner bymixing the components, e.g., in order to obtain coated particles orpellets as for the first component and then by applying one or more filmcoatings as above described.

EXAMPLE 4 Second Component in the Form of a Matrix Tablet Coated withOne Film

[0224] A second component which contains 4.8 mg rivastigmine hta as therivastigmine in the pressed core, e.g. compressed tablet, is coated withan appropriate film. This system, that releases the rivastigmine after apre-determined time when placed in an aqueous fluid, may be produced asfollows:

[0225] A. Preparation of the Core:

[0226] The mass for 5000 cores is prepared as follows. 24 g ofrivastigmine hta are dissolved in 1000 g of purified water. 400 g ofPolyplasdone (polyvinylpolypyrrolidone crosslinked) and 221 g of sodiumchloride are placed in a mixer cum granulation machine, e.g., Diosana®.This mixture is mixed for 5 minutes and the solution of rivastigmine htaadded to this slowly and wet-granulated. The wet mass is then passedthrough a 2 millimeters sieve and dried using a fluidised-bed drier at60° C. After drying, the granules are passed through a sieve of 1millimeter. The granules are weighed and mixed with the appropriateamounts of silica gel, e.g., Aerosil 200®, and microcrystallinecellulose for 20 minutes in a tumbling mixer (Turbula® mixer) andpressed as indicated above into cores each of 178 mg total weight. A 8mm concave punch (R=12) in a tablet press having only one punch, e.g.,Kilian EKO®, may be used.

[0227] B. Preparation of Film Lacquer:

[0228] 4000 compressed cores are coated with a semi-permeable film (ormembrane) of the composition below using the fluidised bed process in acurrent of air, e.g., Glatt-wurster cellulose acetate containing 32%acetyl 139.5 g cellulose acetate containing 39.8% acetyl 145.5 ghydroxypropylmethyl cellulose (HPMC) 15.0 g methylene chloride 6750 gmethanol 750 g

[0229] The film-coating (semi-permeable membrane coating) is effectedwith the above mentioned organic lacquer which contains 4% solid filmconstituent in a solvent mixture of methylene chloride methanol.However, other solvent mixture such acetone/alcohol/water instead ofmethylene chloride/methanol may also be used.

[0230] The cores are coated with layers of film of differingthicknesses, i.e., different weights, for example with approximately 55mg, 70 mg, 80 mg/core, or more for obtaining lag-times of, e.g., 3-4,5-6 or 7-8 hours, and dried in the current of air in a fluidised beddrier for 48 hours at 40° C.

[0231] C. Compositions Quantity/tablet (mg) 1/IngredientsPolyplasdone-XL or Crosspovidone 80.0 Colloidal Silicone Dioxide 5.0Sodium Chloride 44.2 Rivastigmine hta 4.8 Polyplasdone-XL orCrosspovidone 20.0 Avicel PH 102 23.0 Magnesium Stearate 1.0 Core Weight178.0 Cellulose Acetate E320 25.52 Cellulose Aceate 398-10 26.74 HPMC603 2.74 Total Weight 233.0 2/Ingredients Polyplasdone-XL orCrosspovidone 80.0 Colloidal Silicone Dioxide 5.0 Sodium Chloride 44.2Rivastigmine hta 4.8 Polyplasdone-XL or Crosspovidone 20.0 Avicel PH 10223.0 Magnesium Stearate 1.0 Core Weight 178.0 Cellulose Acetate E32032.48 Cellulose Aceate 398-10 34.03 HPMC 603 3.49 Total Weight 248.0

[0232] D. Determination of the Release of Rivastigmine:

[0233] Film-coated tablets as described above having two different filmthicknesses (coated with a film of different weight) are placed in abeaker containing 200 ml of deionised (desalted) water of 37° C., andthe time taken for the breaking of the film (semi-permeable membrane) ofthe two tablets is determined. The details are given in Tables 1 and 2:TABLE 1 drug release DR (%) in water, 50 rpm, film thickness: 55 mgminutes cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0 0.0 0.00.0 120 0.8 0.7 0.9 0.9 0.7 0.7 150 0.7 0.8 0.7 0.7 0.6 0.7 180 0.7 0.80.7 0.7 0.6 0.7 210 53.4 1.4 0.9 0.7 46.9 0.6 240 64.0 64.4 67.0 0.757.5 0.7 300 76.6 81.7 89.5 69.8 69.7 82.1 360 83.1 92.2 94.5 77.7 78.486.8

[0234] TABLE 2 drug release DR (%) in water, 50 rpm, film thickness: 70mg min cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0 0.0 0.00.0 240 0.6 0.4 0.3 0.3 0.3 0.2 270 0.5 1.0 1.3 0.8 0.5 0.6 300 45.6 0.342.9 46.8 0.5 2.2 330 63.7 59.1 61.8 61.0 33.0 45.1 360 72.7 71.2 69.870.1 51.2 56.0 420 84.7 84.0 81.6 81.8 65.7 69.5

EXAMPLE 5 Second Component in the Form of a Matrix Tablet Coated withTwo Films

[0235] A. Preparation of the Core:

[0236] The mass for 70,000 cores is prepared as follows. 336 g ofrivastigmine hta is dissolved in about 6400 g of purified water and 12 gof alpha-tocopherol is dissolved in about 388 g ethanol (in case of BHTa similar solution would also be prepared). 6938 g of Polyplasdone-XL,1660 g of Microcrystalline Cellulose, 3094 g of Sodium Chloride(previously milled), and 350 g of colloidal silicon dioxide (Aerosil200) are sieved through a 1600 μm sieve and are transferred into a 75 LCollette Gral High Shear Mixer. In the Collette Gral the dry powders aremixed for one minute with Plow at slow speed and Chopper off. After thatthe alpha-tocopherol solution and the rivastigmine solutions are addedslowly with the Plow and Chopper both operating at a slow speed.Additional purified water is added to form granules. After that theCollette Gral is operated for 2 minutes with the Plow at slow andChopper at fast speeds. Then the granules are dried in the fluidized beddryer with inlet air temperature of about 70° C., till a Loss on Dryingof less then 4% is achieved. After that the dried granules are sievedthrough an 800 μm sieve and mixed with the magnesium stearate(previously sieved) for 5 minutes in a free fall blender. This mixtureis then compressed into tablets of 178 mg using oblong tooling of size10×5.2 mm using a suitable tablet press.

[0237] B. Film Coating:

[0238] First the two solutions for the two films are prepared. 499 g ofCellulose Acetate 398-10, 499 g of Cellulose Acetate 320S and 53 g of 3cps HPMC are dissolved in a solvent mixture of 70% Acetone, 20% Ethanoland 10% Purified Water to form a 7.5% solution by weight of solidcomponents. 441 g of Ethyl Cellulose N10 and 49 g of 5 cps HPMC aredissolved in a solvent mixture of 60% Acetone and 40% Ethanol to form a5% solution by weight of the solid components. Up to 5% extra solutionmay be prepared to account for the loss from spray drying during thecoating process. The tablets prepared above are coated in a suitablePerforated Coating Pan by spraying first the Cellulose Acetate solutionand then the Ethyl Cellulose solution, to target film weights. Othersolvent systems such as methylene chloride/methanol may also be used.

[0239] C. Compositions Ingredients Quantity/tablet (mg) Rivastigmine hta4.8 4.8 Sodium Chloride 44.2 44.2 Avicel PH 102 23.712 23.712 PVPP-XL99.11 99.11 a-tocopherol 0.178 0.178 Aerosil 200 5.0 5.0 MagnesiumStearate 1.0 1.0 Core Weight 178.0 178.0 Cellulose Aceate 398-10 7.1257.125 Cellulose Acetate E320 7.125 7.125 HPMC 603 0.750 0.750Ethylcellulose N10 4.5 6.3 HPMC 5 cps 0.5 0.7 Total Weight 198 200

[0240] In a further composition a-tocopherol may be replaced by BHT(butylated hydroxytoluene): Ingredients Quantity/tablet (mg)Rivastigmine hta 4.8 Sodium Chloride 44.2 Avicel PH 102 23.0 PVPP-XL99.11 BHT 0.890 Aerosil 200 5.0 Magnesium Stearate 1.0 Core Weight 178.0Cellulose Aceate 398-10 9.5 Cellulose Acetate E320 9.5 HPMC 603 1.0Ethylcellulose N10 2.7 HPMC 5 cps 0.3 Total Weight (mg) 201

[0241] D. Determination of the Release of Rivastigmine: TABLE 1 drugrelease DR (%) in water, 50 rpm, oblong tablet (approximate size 10.25mm (millimeters) × 5.5mm × 4.80-4.85mm) minutes cell 1 cell 2 cell 3cell 4 cell 5 cell 6 240 0.0 0.0 0.0 0.0 0.0 0.0 300 0.0 0.0 0.0 0.0 0.00.0 360 58.1 0.0 0.0 59.8 0.0 0.0 420 89.6 62.4 58.9 83.4 0.0 60.6 48092.0 96.0 85.4 97.2 97.1 85.5 540 99.0 97.9 95.2 100.9 95.8 97.6 60099.4 100.2 102.7 101.0 100.2 99.9 660 100.4 100.9 103.0 102.3 102.1102.5 720 102.1 101.8 103.2 99.4 104.2 101.6

[0242] TABLE 2 drug release DR (%) in water, 50 rpm, round tablet(approximate size: 8,57 × 5,58 millimeters) minutes cell 1 cell 2 cell 3cell 4 cell 5 cell 6 240 0.0 0.0 0.0 0.0 0.0 0.0 300 0.0 0.0 0.0 0.096.5 0.0 360 92.5 0.0 0.0 0.0 99.4 0.0 420 100.9 0.0 0.0 0.0 99.8 0.0480 101.6 89.5 0.0 0.0 100.3 0.0 540 101.5 98.0 0.0 0.0 100.2 88.7 600100.9 100.1 94.4 0.0 99.4 97.0 660 101.7 101.7 100.1 0.0 98.8 101.0 720102.1 100.7 101.8 76.2 99.2 102.1

EXAMPLE 5 Capsule Filing

[0243] The capsule filling mixture comprising first and second componenttogether (or alone if desired) is filled on a automatic capsule fillingmachine (Zanasi® LZ 5) into empty hardgelatine capsule shells (CONISNAP®6 dimple, size 3). The nominal fill weight is as mentioned above. Theprocess parameters are as follows:

[0244] speed: 3000 HK/h

[0245] dosator/piston:

[0246] size: #4

[0247] height: 12-14 mm

[0248] vacuum: 0.7 bar

[0249] feed hopper: none

1. A pharmaceutical composition comprising a first component comprisinga first active agent dose wherein on contact with water 70 to 95% ofsaid dose is released within 3 to 4 hours, and a second componentcomprising a second active agent dose, a water soluble osmosis inducingagent and a water swellable excipient, said second component having awater permeable coating which, in use on contact with water, rupturesafter a delay, and releases the active agent.
 2. A pharmaceuticalcomposition according to claim 1 , wherein the coating in the secondcomponent is a semi-permeable membrane.
 3. A pharmaceutical compositionaccording to claim 1 or 2 wherein the second component releases aneffective dose of the active agent 6 to 12 hours after ingestion.
 4. Apharmaceutical composition according to any one of claims 1 to 3 whereinthe first component comprises a cellulose derivative coating.
 5. Apharmaceutical composition according to claim 4 wherein the cellulosederivative coating comprises ethyl cellulose and hydroxypropylmethylcellulose.
 6. A pharmaceutical composition according to any one ofclaims 1 to 3 wherein the first component comprises the active agent ina matrix.
 7. A pharmaceutical composition according to claim 6 whereinin the first component the active agent is in a hydrophilic gel formingsubstance.
 8. A pharmaceutical composition according to claim 7 whereinthe hydrophilic gel forming substance is present in a ratio of 10 to 50%by weight of the first component.
 9. A pharmaceutical compositionaccording to claim 7 or 8 wherein the hydrophilic gel forming substancecomprises hydroxypropylmethylcellulose having a viscosity of 100,000mPa-s.
 10. A pharmaceutical composition according to any one of claims 1to 9 wherein the second component has the following releasecharacteristics in water: time (minutes) amount (percentage) 0 0-1 1200-1 180 0-1 240  0-75 300  0-95 360 >99.


11. A pharmaceutical composition according to any one of claims 1 to 10wherein the active agent is rivastigmine.
 12. A pharmaceuticalcomposition according to any one of claims 1 to 11 comprising from 0.5to 25% by weight of rivastigmine as active agent of the totalcomposition.
 13. A pharmaceutical composition according to any one ofclaims 1 to 12 wherein the second component comprises a second coating.14. A pharmaceutical composition comprising rivastigmine adapted so thatin use on oral administration a therapeutically effective dose ofrivastigmine is released only after 6 hours.
 15. A pharmaceuticalcomposition capable of releasing on administration twice atherapeutically effective dose of rivastigmine at different intervalsupon oral administration.
 16. A pharmaceutical oral controlled releasetablet composition comprising rivastigmine.
 17. A pharmaceuticalcomposition comprising Rivastigmine having the following releasecharacteristics in water: time (minutes) amount (percentage) 30  1-40 6010-60 120 40-80 180 60-90 240 65-95 300 70-99 360 75-99 420 >80.


18. A controlled release, oral pharmaceutical composition containingrivastigmine having the following release characteristic in water orartificial stomach juices: time (minutes) amount (percentage) 30 1-8 6015-25 120 45-70 180 75-90 240 92-95 300 95-98 360 97-99 420 >99.


19. A controlled release, oral pharmaceutical composition containingrivastigmine having the following release characteristic in water orartificial stomach juices: time (minutes) amount (percentage) 30  5-2560 25-45 120 50-70 180 65-80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95.


20. A controlled release, oral pharmaceutical composition containingrivastigmine having the following release characteristic in water orartificial stomach juices: time (minutes) amount (percentage) 30 25-4060 45-65 120 65-85 180 75-95 240 75-96 300 85-97 360 87-98 420 90-98 480 90-99.


21. A controlled release, oral pharmaceutical composition containingrivastigmine wherein in use 50 to 80% of said rivastigmine is releasedin artificial stomach juices within 3 hours.
 22. A composition accordingto any one of claims 16 to 21 comprising coated particles.
 23. Acomposition according to any one of claims 16 to 22 comprising coatedpellets.
 24. A composition according to claim 22 or 23 wherein thecoating comprises a cellulose derivative.
 25. A composition according toclaim 24 wherein the cellulose derivative comprises ethyl cellulose andhydroxypropyl methylcellulose.
 26. A pharmaceutical compositionaccording to claim 16 or 17 wherein rivastigmine is in a hydrophilicswellable substance.
 27. A pharmaceutical composition according to claim26 wherein the hydrophilic swellable substance compriseshydroxypropylmethylcellulose 100,000 cps.
 28. A pharmaceutical oralcontrolled release tablet composition comprising rivastigmine having thefollowing release characteristic in water or artificial stomach juices:time (minutes) amount (percentage) 30 28-35 60 40-55 120 58-75 180 70-90240 80-95 300 88-98 360 >92.


29. A pharmaceutical oral controlled release tablet compositioncomprising rivastigmine wherein in use 60 to 90% of said rivastigmine isreleased in artificial stomach juices within 3 hours.
 30. Use ofrivastigmine and excipients as defined in any one of claims 1 to 29 inthe manufacture of a medicament for the treatment of patients with mildto moderately severe Dementia of the Alzheimer's type by oraladministration.
 31. A pharmaceutical composition comprising a corecoated with two films, the first inner film being a semi-permeable towater or body fluids film applied directly on said core and comprisingcellulose acetate, the second outer film being a permeable to water orbody fluids film comprising ethylcellulose.